Effects of concurrent cartilage procedures on cartilage regeneration in high tibial osteotomy: a systematic review

Purpose This systematic review aimed to evaluate the effects of concurrent cartilage procedures on cartilage regeneration when performed alongside high tibial osteotomy (HTO). Materials and methods The systematic review followed the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). A comprehensive search was conducted on databases including PubMed, Embase, Cochrane Library, and Google Scholar, covering articles published until August 31, 2023. Results Sixteen studies (1277 patients) revealed that HTO, with or without concurrent cartilage procedures, leads to cartilage regeneration based on the International Cartilage Repair Society (ICRS) grade during second-look arthroscopy. No concurrent procedure showed improvement in ICRS grade (mean difference: − 0.80 to − 0.49). Microfracture (mean difference: − 0.75 to − 0.22), bone marrow aspirate concentrate (BMAC) (mean difference: − 1.37 to − 0.67), and human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) (mean difference: − 2.46 to − 1.81) procedures also demonstrated positive outcomes. Clinical outcome assessments for each cartilage procedure were also improved during postoperative follow-up, and no specific complications were reported. Conclusions HTO with or without concurrent cartilage procedures promotes cartilage regeneration observed during second-look arthroscopy, with improved clinical outcomes. Future randomized controlled trials on the same topic, along with subsequent meta-analyses, are necessary for conclusive findings. Supplementary Information The online version contains supplementary material available at 10.1186/s43019-024-00221-w.


Introduction
High tibial osteotomy (HTO) is a surgical procedure often used to treat unicompartmental knee osteoarthritis, particularly when realigning the knee joint becomes necessary [1][2][3].This procedure involves modifying the alignment of the tibial plateau to reduce excessive load on the affected joint compartment, thereby alleviating pain and potentially slowing osteoarthritis progression [4][5][6].Recently, the combination of HTO and concurrent cartilage procedures has gained considerable attention in orthopedic surgery [7,8].
Concurrent cartilage procedures performed alongside HTO primarily aimed to enhance cartilage regeneration and overall joint preservation.These procedures involve several techniques.Subchondral drilling (SD) or microfracture (MFX) involves the creation of small holes or fractures in the subchondral bone beneath the articular cartilage [9,10].These processes stimulate the release of bone marrow cells and growth factors, fostering fibrocartilage formation in the damaged areas.These outcomes may be attributed to insufficient stimulation of function and a lower number of recruited mesenchymal stem cells (MSCs) [11,12].
In bone marrow aspirate concentrate (BMAC) augmentation, bone marrow is extracted, stem cells and growth factors are concentrated, and the resulting mixture is used to facilitate cartilage repair [13].BMAC augmentation depends on the inclusion of various growth factors and pluripotent stromal cells that induce MSCs differentiation into chondrocytes [14].This process potentially produces native, hyaline-like cartilage.
Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) utilize stem cells from human umbilical cord blood and offer potential contributions to cartilage repair and regeneration when introduced into the knee joint [15].hUCB-MSCs are recognized for their low immunogenicity and the convenience of being a noninvasive collection method.Furthermore, they demonstrate a robust expansion capacity, ensuring a sufficient cell supply for effective treatment [16].
Based on previously published meta-analyses and systematic reviews, Park et al. [17] conducted a metaanalysis comparing cartilage regeneration and clinical scores between BMAC and hUCB-MSC therapies when performed with HTO. Lee et al. [7] and Kehlenberg et al. [18] performed meta-analyses of the clinical effects of concurrent cartilage procedures performed with HTO.To the best of our knowledge, this is the first meta-analysis and systematic review investigating the second-look arthroscopy results for all types of concurrent cartilage procedures performed alongside HTO.This systematic review and meta-analysis aimed to critically evaluate the effect of concurrent cartilage procedures on cartilage regeneration when performed alongside HTO.By synthesizing evidence from relevant studies, we provide a comprehensive perspective on the efficacy of these concurrent procedures in enhancing cartilage regeneration and improving clinical outcomes following HTO.

Search strategy
The review was registered a priori in the PROS-PERO prospective register of systematic reviews (ID: CRD42023474067) and conducted according to a predefined protocol and in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.A comprehensive search strategy was devised to identify the relevant studies.We systematically searched PubMed, Embase, Cochrane Library, and Google Scholar for articles published until August 31, 2023.The search terms used were [("HTO" OR "high tibial osteotomy" OR "proximal tibial osteotomy") AND (("second look" OR "second-look") AND "arthroscopy") AND "knee" AND "osteoarthritis"[mesh]].

Identification of eligibility
Two independent reviewers screened the search results to determine eligibility.The inclusion criteria were as follows: (1) adult patients diagnosed with OA; (2) studies that included interventions, such as HTO with concurrent cartilage procedures; (3) studies that reported the results of second-look arthroscopy; and (4) studies with a minimum follow-up period of 12 months.The exclusion criteria were as follows: (1) non-English articles; (2) studies with incomplete data; and (3) studies that did not meet the aforementioned criteria.
For conducting a high-quality systematic review, it is desirable to include studies with a high level of evidence.However, pilot search results revealed a limited number of randomized controlled trials addressing the topic, with only one identified.Consequently, to draw appropriate conclusions, the inclusion criteria were set as outlined above.For studies conducted by the same study group where patient groups were expected to overlap, only studies with a higher level of evidence or lower bias risk were included.Two independent reviewers screened the search results to determine eligibility.

Data extraction
Two reviewers independently extracted data, including the first author, publication year, study design, level of evidence, type of osteotomy, type of concurrent cartilage procedure, sex, age, body mass index, sample size, preoperative International Cartilage Repair Society (ICRS) grade, mean follow-up duration, clinical assessments, postoperative ICRS-Cartilage Repair Assessment grade, postoperative Koshino stage, postoperative histological assessments, postoperative magnetic resonance observation of cartilage repair tissue (MOCART) score, and reported complications.Data pooling for the cartilage regeneration assessment was conducted with a focus on the outcomes of the medial compartment, which was the target of the cartilage procedure.
To assess the risk of bias, we used the methodological index for non-randomized studies (MINORS), consisting of 12 categories for comparative studies and eight categories for non-comparative studies.Each category received a rating of 0 (if not reported), 1 (if reported but inadequate), or 2 (if reported and deemed adequate).Quality of non-randomized-controlled trials was evaluated by the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool.

Statistical analysis
Statistical analyses were conducted using the appropriate meta-analysis techniques.Descriptive statistics, including the mean and standard deviation for numerical variables, were recorded.In cases where the studies did not provide a standard deviation in their results, we calculated it based on other provided statistical values, following the method outlined by Furukawa et al. [19].For the analysis of continuous outcome measures of the assessment of cartilage using the ICRS grade, we utilized the mean differences (MD) with 95% confidence intervals (CIs).We based our analysis on the ICRS grade as the primary outcome for cartilage regeneration.A subgroup meta-analysis was attempted for treatment approaches reported in two or more studies.Heterogeneity was assessed using the I 2 statistic.I 2 was calculated after the inclusion of subsequently poorer quality studies in a cumulative meta-analysis for a sensitivity analysis.The subgroups used in the analysis included no concurrent procedure, MFX, BMAC, and hUCB-MSC.Qualitative comparisons were made between the data, and pooling was avoided due to heterogeneity between included studies.Only the results of studies included in this review were presented using forest plots.All statistical analyses and data visualization were performed using R software (version 4.2.1;R Foundation, Vienna, Austria).

Methodological quality assessment of included studies
We assessed the methodological quality of the selected studies, identifying different levels.One study was at level 2 [35], eight at level 3 [20,21,25,30,[32][33][34], and nine at level 4 [22-24, 26-29, 31].For comparative studies, the average MINORS score was 19.4 ± 1.4, based on the data from eight studies.Non-comparative studies had an average MINORS score of 10.5 ± 1.6 across eight studies.Additional file 1: Table S1 provides further details on the MINORS scores.The quality of non-randomized controlled trials was assessed using the ROBINS-I tool, and only one study was rated as having an overall low risk of bias.The assessment results using the ROBINS-I tool are presented in Additional file 1: Table S2.

ICRS grade
The results of preoperative and second-look arthroscopy ICRS grade were reported in 13 studies (Table 3) [20,[22][23][24][25][26][27][28][29][30][31][32]35].We attempted a meta-analysis on the ICRS grade results from preoperative and second-look arthroscopy assessments.Substantial heterogeneity was observed (I 2 = 94%, τ 2 = 1.4972,P < 0.001).A sensitivity analysis was conducted to evaluate whether the inclusion of lower quality studies significantly impacted the heterogeneity of the meta-analyses (Additional file 1: Table S3).However, this analysis resulted in only minimal changes in the I 2 statistic.Therefore, data pooling was not performed, and the degree of cartilage regeneration in second-look arthroscopy for each cartilage procedure was presented in a forest plot (Fig. 2).Studies were grouped into subcategories based on the treatment methods: no concurrent procedure, MFX, BMAC, and hUCB-MSC.
The results for the no concurrent procedure were reported in five studies [22,24,26,30,31], showing an improvement in ICRS grade with a mean difference ranging from − 0.80 to − 0.49 between the preoperative and second-look time points.For MFX, the results from four studies indicated a mean difference ranging from − 0.75 to − 0.22 [28,30,32,35].BMAC results were reported in two studies, with a mean difference range of − 1.37 to − 0.67 [25,32].The hUCB-MSC results, reported in four studies, showed a mean difference range of − 2.46 to − 1.81 [23,25,27,29].
Additionally, Shon et al. [20] reported that SD with particulated costal hyaline cartilage allograft (PCHCA) showed a significantly better cartilage status compared to subchondral drilling alone based on the ICRS-CRA grading system (P < 0.001).Kim et al. [35] compared the results of MFX alone with MFX with collagen augmentation.In the MFX with collagen augmentation group, three patients (21.4%) were classified as normal (grade 1), nine (64.3%) as nearly normal (grade 2), and two (14.3%) as abnormal (grade 3).

Koshino staging
The results of postoperative Koshino staging were reported in five studies (Table 3) [20,25,27,32,34].Shon et al. [20] found that SD with PCHCA resulted in the following stage distribution: stage A (0 cases), stage B (12 cases), and stage C (39 cases).In the SD alone, the distribution was stage A (4 cases), stage B (41 cases), and stage C (6 cases).The findings demonstrated a significant improvement in the Koshino stage with SD and PCHCA (P < 0.001).
Kim et al. [34] reported 25 cases of stage A, 63 cases of stage B, and 34 cases of stage C in the group without concurrent cartilage procedures performed.Chung et al. [27] found 0 case of stage A, 12 cases of stage B, 27 cases of stage C-1, and 10 cases of stage C-2 in the hUCB-MSC treatment group.

MOCART score
Postoperative MOCART scores were reported in three studies (Table 3) [28,30,35].Lee et al. [30] reported Fig. 1 PRISMA flow diagram for the systematic review scores of 41.8 ± 18.6 for the MFX group and 31.8 ± 19.8 for the group without procedure.Significantly higher scores were found in the MFX group than in the no-procedure group (P = 0.023).Kim et al. [35] reported scores of 45.4 ± 11.5 for the MFX group and 64.6 ± 14.1 for the MFX with collagen augmentation group.They observed a significantly higher score in the MFX with collagen augmentation group than in the MFX group (P = 0.001).Iida et al. [28] reported a score of 69.2 ± 10.1 for the MFX group.

Histological assessment
Histological assessments were reported in two studies [22,35].Wu et al. [22] found that HTO without concurrent cartilage procedures significantly upregulated the expression of p-ERK1/2 at the protein level in patients with knee osteoarthritis compared with that in the control group.Kim et al. [35] reported ICRS II scores of 885.4 for the MFX group and 1053.2 for the MFX with collagen augmentation group.They observed a significantly higher score in the MFX with the collagen augmentation group (P = 0.002).

Discussion
This systematic review aimed to critically assess the effect of concurrent cartilage procedures when performed alongside HTO.It included 16 studies involving 1277 patients.The key finding of this study lies in comprehensively examining the effectiveness of each cartilage procedure by investigating all studies that reported second-look arthroscopy results.The results reported in terms of ICRS grade and Koshino grade were compiled; and although there were variations in the degree of improvement, it was confirmed that all concurrent procedures performed with HTO had an effect on cartilage regeneration.Considering the level of evidence and heterogeneity in the studies included in this review, it was deemed inappropriate to compare the overall treatment effect of each procedure through data pooling, and thus, this was not conducted.
In previous meta-analyses and systematic reviews focusing on concurrent cartilage procedures performed alongside HTO, Park et al. [23] analyzed the ICRS grade for BMAC and hUCB-MSC therapies and reported significantly superior cartilage regeneration in the hUCB-MSC group.Lee et al. [7] noted that one study found no significant differences in fibrocartilage formation between the HTO-only and HTO-plus-arthroscopic drilling groups [33].In studies involving concurrent abrasion arthroplasty and human autologous cultureexpanded bone marrow mesenchymal cell transplantation, the control groups exhibited more favorable healing outcomes compared to the case groups [36].
The MFX technique recruits bone marrow elements to repair cartilage defects.However, it lacks a stable long-term efficacy and is ineffective in the treatment of large cartilage defects [37].Mithoefer et al. [38] reported that a review of 28 trials confirmed deterioration within 2 years, highlighting limitations such as the absence of hyaline tissue repair, variable cartilage volume restoration, and potential functional decline.Concentrated MSCs from autologous bone marrow offer an emerging approach for treating cartilage disease [32].This method simplifies MSC acquisition, enabling the entire process from harvesting to transplantation in a single operation [39].BMACs contain growth factors that promote cartilage regeneration and MSC adhesion.BMACs also possess immunomodulatory and anti-inflammatory properties that promote cartilage restoration.However, achieving consistent cell numbers and concentrations can be challenging as centrifugation procedures are performed in the operating field.
hUCB-MSCs are derived from the umbilical cord blood and have emerged as a promising treatment for cartilage regeneration.Studies have reported improved outcomes in knee osteoarthritis after hUCB-MSC application [40].Cells obtained from donors are typically expanded in culture before being injected into the affected joint or used in combination with other procedures.Notably, hUCB-MSCs have higher proliferation rates and more than 1000-fold greater expansion capacity compared to BMACs.This may affect the effectiveness of cartilage regeneration observed during second-look arthroscopy, depending on the chosen treatment approach.
In addition to the ICRS evaluation of cartilage regeneration, when examining other assessments related to cartilage regeneration, radiographical evaluation of cartilage regeneration was reported using MOCART scores.Lee et al. [30] reported a significantly higher MOCART score in the MFX group than in the noprocedure group.Kim et al. [35] also reported a significantly higher score in the MFX with collagen augmentation group than in the MFX-only group.With regard to the histological evaluation, Kim et al. [35] reported a significantly higher ICRS II score in the MFX with collagen augmentation group than in the MFX-only group.
In all the included studies, improvements in postoperative clinical scores were observed compared to preoperative clinical scores.The primary outcome of this study was the degree of cartilage regeneration confirmed during second-look arthroscopy.Additionally, considering the substantial heterogeneity and level of evidence in the clinical scores reported in the studies included in this research, a meta-analysis for these parameters was not conducted.Apart from the improvement noted in postoperative clinical scores compared to preoperative scores, the overall effects of each cartilage process generally yielded mixed results.These findings were in line with previous meta-analyses.
In accordance with the research conducted by Lee et al. [7] which investigated the clinical effects of concurrent cartilage procedures conducted alongside HTO, studies included in their analysis showed no statistically significant differences in clinical results between groups.One study that performed MSC injection as a concurrent procedure reported additional treatment effects on the IKDC, Lysholm, and Tegner scores.HTO patients with MFXs showed worse HSS scores compared to the control group.Similarly, a meta-analysis conducted by Park et al. [17] examining the clinical effects of hUCB-MSCs and BMACs reported no significant differences in IKDC, WOMAC, KSS pain, or KSS function between the two groups.Due to the fact that HTO was performed for all patients included in this study, the proportion of the contribution of cartilage procedures to the improvement in clinical outcomes was not clearly defined.This could be clarified through the analysis of results from randomized controlled trials targeting these interventions in the future.
The role of HTO is not only to reduce symptoms in patients with OA but also to slow down the progression  to a state requiring total knee arthroplasty (TKA) in end-stage OA [1].The follow-up period of the studies included in this research ranged from about 1 to 3 years, which generally corresponds to a short term.The review was conducted focusing on the degree of improvement in cartilage regeneration and clinical outcomes during this period.Consequently, there were inherent limitations in verifying the effectiveness of HTO in further delaying the advancement of OA.Thus, in order to assess how well HTO achieves its other primary objective of postponing the need for TKA, it seems essential to review long-term follow-up studies that incorporate survival analysis.Such research, if undertaken, should encompass radiographic evaluations that go beyond mere confirmation of cartilage regeneration, including serial follow-up data such as the KL grade, to monitor OA progression comprehensively.

P-value
Cost-effectiveness is also a crucial issue in the selection of treatment methods.Especially, since biologics like stem cells are used in cartilage procedures, the cost can vary significantly depending on the treatment method.While there may be differences between medical institutions, in South Korea, undergoing HTO alone can start at a cost of around 1000 dollars with health insurance applied.In contrast, adding hUCB-MSC therapy can incur additional costs ranging from 5000 to 7000 dollars or more, and national health insurance typically does not apply in such cases.Due to the heterogeneity identified in this study, a clear superiority of concurrent cartilage procedures has not been established.Moreover, considering that significant improvements in cartilage regeneration and clinical outcomes were observed even in cases of HTO without concurrent cartilage procedure included in this study, it can be considered that there are benefits of HTO alone from a cost-effectiveness standpoint.
The limitations of this study should be acknowledged.First, the majority of the included studies were classified as level 3 or 4 evidence.This categorization was unavoidable due to the limited availability of randomized controlled trials focusing on this specific topic, thereby posing a challenge in obtaining more robust data.Second, the presence of high heterogeneity among studies was observed, leading to the decision not to conduct a pooled analysis.If the issues of a lack of high-level studies and significant heterogeneity are resolved, methods such as network meta-analysis could be utilized for comparing and ranking treatment methods.This would serve as a powerful tool for drawing clear conclusions on this topic.Third, our analysis was exclusively centered on concurrent procedures for medial compartment osteoarthritis during HTO.This raises the possibility that changes in other compartments, such as the patellofemoral joint, may influence clinical outcomes.To address this concern, we intend to conduct future studies that explore other joint compartments.Fourth, some studies lacked a control group consisting of patients undergoing HTO alone.This omission may introduce bias when interpreting the results.Finally, as mentioned in the previous discussion, the follow-up periods in the reviewed studies were not sufficiently extended to comprehensively assess longterm clinical outcomes and survival rates.
In conclusion, HTO performed with or without a concurrent cartilage procedure appears to result in cartilage regeneration observed during second-look arthroscopy compared to the initial state.Clinical outcome assessments also showed improvement, and specific complications associated with concurrent cartilage procedures were not reported.The extent of cartilage regeneration confirmed during second-look arthroscopy varied to some degree for each concurrent cartilage procedure.However, considering the heterogeneity and level of evidence in the studies included in this research, a pooled analysis was not conducted to draw definitive conclusions.Future randomized controlled trials on the same topic, along with subsequent meta-analyses, will be necessary to derive conclusive findings.

Fig. 2
Fig. 2 Forest plot of effects of concurrent cartilage procedures based on the International Cartilage Repair Society (ICRS) grade of second-look arthroscopy.Pre-OP preoperative, SD standard deviation, MD mean difference, CI confidence interval, MFX microfracture, BMAC bone marrow aspirate concentrate, hUCB-MSC human umbilical cord blood-derived mesenchymal stem cell

Table 3
Assessment of cartilage regeneration in included studiesICRS International Cartilage Repair Society, Pre-OP preoperative, Post-OP postoperative, MOCART magnetic resonance observation of cartilage repair tissue, SD subchondral drilling, PCHCA particulated costal hyaline cartilage allograft, N/A not applicable, hUCB-MSC human umbilical cord blood-derived mesenchymal stem cell, BMAC bone marrow aspirate concentrate, MFX microfracture

Table 4 (
IKDC International Knee Documentation Committee, WOMAC Western Ontario and McMaster Universities Arthritis Index, KSS Knee Society score, Pre-OP preoperative, Post-OP postoperative, MOCART magnetic resonance observation of cartilage repair tissue, SD subchondral drilling, PCHCA particulated costal hyaline cartilage N/A not applicable, SVF stromal vascular fraction, hUCB-MSC human umbilical cord blood-derived mesenchymal stem cell, BMAC bone marrow aspirate concentrate, MFX microfracture continued)